The tau H1 association in 4R tauopathies, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), is fundamental to their etiology, yet the underlying mutation(s) and functional effects on tau biology remain enigmatic. It is remarkable, though more controversial, that a similar tau H1 association exists for Parkinson's disease (PD), clearly a very different disorder. However, tau is a consistent feature of the alpha-synuclein/Lewy pathology in the olfactory bulb and amydala of PD cases and a subset of PSP patients have Lewy bodies present. Animal models have also questioned the classical defining role of tangles in neurotoxicity in tauopathies. Our Preliminary data, employing the relatively isolated population of central Norway, shows unequivocally that: l) tau H1 variants are associated with Parkinson's disease; 2) tau H1 is a misnomer and is a haplotype clad, and; 3) genetic analysis within this sample is sufficiently powerful to identify the functional mutation responsible. Our application has three Aims: 1) High-resolution genetic analysis of tau H1 including assessment of linkage disequilibrium, haplotype cladistics and association to clinical disease; 2) Replicating and extending findings from a homogeneous Norwegian isolate to more heterogeneous US samples, including a PD case/control cohort and pathologically confirmed synucleinopathy and tauopathy, and; 3) Genomic and functional analysis of tau haplotypes and the variants which define them. Genetic insights from the work proposed will have major ramifications for disease nosology, diagnostic testing and patient treatment. As previously, we would clone the disease-associated variants identified and make constructs available to the wider research community for the development of in-vivo models, in which the disease etiology may be further unraveled and treatments developed.